R. T. Walker

Sister chromatid exchange induced by anti-herpes drugs.

The rate of sister chromatid exchange induced by several anti-herpes agents was measured to assess their potential mutagenicity. The agents--5-iodo-deoxyuridine (IDU), 5-trifluoromethyl-deoxyuridine (TFT), and [E]-5-(2-bromovinyl)-deoxyuridine (BVDU)--were incubated at various concentrations with human lymphocytes and fibroblasts, and that rate of sister chromatid exchanges was measured. In lymphocytes and fibroblasts BVDU and IDU did not induce exchange except at concentrations of 50 mg/l, while TFT increased the rate of exchange at a concentration of 0.5 mg/l. The rate of sister chromatid exchange is a sensitive index of chromosomal damage, and these findings provide information on the safety of some of the antiherpes agents tested. TFT increased the rate of exchange at a concentration that coincides with its minimal antiviral concentration, but BVDU did not induce exchange at therapeutic concentrations.

HEPT: From an investigation of lithiation of nucleosides towards a rational design of non-nucleoside reverse transcriptase inhibitors of HIV-1

Publisher Summary This chapter presents the alpha lithiation reaction at the base moiety of purine, imidazole, and pyrimidine nucleosides for the synthesis of their analogs and an anti-HIV-1 (Human Immunodeficiency Virus Type 1) lead compound HEPT which resulted from the lithiation studies. Lithiation chemistry of aromatic compounds started with a halogenlithium exchange reaction reflecting the historical finding that an aryllithium can be generated by treatment of an aryl halide with alkyllithium. The anti-HIV-1 activity of HEPT is only marginal when compared with that of AZT and ddC, but HEPT was found to be much less toxic than these nucleoside derivatives. In terms of activity (EC 50 ) and cytotoxicity (CC 50 ), HEPT is almost comparable to ddA. A salient feature of this compound lies in its highly specific antiviral property. When the activity of HEPT was examined by changing the virus as well as the cells, HEPT was uniformly active to various strains of HIV-1, but not to other retroviruses, including HIV-2, and other DNA viruses.